Abstract

Introduction: The Hedgehog (Hh) signaling plays essential role in transcription regulation and embryonic development. In many cancers including lung cancer, it is related to carcinogenesis and poor prognosis. This signaling also mediates epithelial to mesenchymal transition (EMT) by paracrine mechanism in various diseases. We aim to study the interaction between Hedgehog and EMT pathway and its clinical implication in non-small cell lung cancer (NSCLC).

Method: Total 271 cases of NSCLC who received surgical resection in Yeouido St. Mary’s Hospital between 1997 and 2011 were included. For immunohistochemical analysis of Hh and EMT related proteins, 4um sections were sliced from tissue microarray. Hh signaling proteins including Sonig hedgehog (Shh), Patched (Ptch), Smoothened (Smo), Glioma-associated oncogene (Gli-1) and Suppressor of fused (Sufu), and EMT associated molecules including E-cadherin and vimentin were analyzed. Staining intensity (IS) was estimated as follows 0 (no staining), +1 (weak), +2 (distinct), +3 (strong). Intensity score (IS) ≥1 was defined as positive. Medical record was retrospectively reviewed. The study was approved by the institutional review board the hospital.

Result: The median age was 63 (18-84) years, and 65.3% were male. Squamous cell carcinoma was diagnosed in 113 (41.7%), adenocarcinoma in 153 (56.5%), and mixed type in 153 (56.5%). Stage 1 and 2 were 46.9% and 30.6%, respectively, and 8 cases had distant metastasis. The Hh proteins showed positive correlation each other. For EMT, the expressions of Hh protein was significantly correlated with tumoral and stromal positivity of vimentin, and inversely with positivity of E-cadherin (P = 0.002 and P = 0.028, respectively). The expression of Hh proteins were significantly associated with lymph node metastasis along with large tumor size (P = 0.021 and P = 0.035, respectively). In survival analysis, expressions of Shh and Gli1 were independent predictor of disease free survival and cancer-specific survival (P = 0.007 and P = 0.025, respectively).

Conclusion: Expression of Hh protein is associated with epithelial-mesenchymal transition and associated with poor prognosis in NSCLC.